Opioid antagonists have been patented for inducing anorexia (Smith, U.S. Pat. No. 4,217,353, 1980; U.S. Pat. No. 4,477,457, 1984), and they also have been patented for treating anorexia (Huebner, U.S. Pat. No. 4,546,103, 1985). Both results are valid. The antagonists can also reduce binge eating and also the purging associated with bulimia, but normal eating, too. Narrowly limited experiments have found evidence for each of these effects. When put into long term practice, however, the different effects counteract each other and cause complications. For example, as Smith pointed out, the only clinical trial using naloxone for anorexia was inconclusive because they coupled the treatment with giving a hypercaloric diet (Moore et al., 1981).
Unfortunately, the methods used and previously proposed for the treatment of eating disorders are unable to separate these various actions. Consequently, the antagonists have produced mixed clinical results, have not received FDA approval for use with eating disorders, and currently are not being used clinically for such purposes.
In contrast, in the field of alcoholism and drug addiction treatment, I proposed a method in which the antagonists specifically remove the addictive behavior (Sinclair, U.S. Pat. No. 4,882,335, Nov. 21, 1989; U.S. Pat. No. 5,587,381, Dec. 24, 1996). Our double-blind placebo-controlled clinical trial has shown naltrexone is effective when used in accord with this method but not when use otherwise (Heinälä et al., 2001). Similar results have been obtained in nearly all trials (Sinclair, 2001). Naltrexone has been approved by the FDA for use in alcoholism treatment. Going one step further, I improved the method into a procedure of “selective extinction” that not only removes alcoholism and drug addiction but also enhances other competing behaviors (Sinclair, U.S. Pat. No. 5,587,381, 1996; Sinclair et al., 1994; Sinclair, 2001). Especially here in Finland where naltrexone is used in this selective manner, it has become a major factor in the treatment of alcoholism.
The present invention takes this selective extinction method for separating the actions of opioid antagonists on different behaviors and contemplates applying it to the treatment of eating disorders. In addition, several innovations are proposed to optimize the method to the eating disorder field and which then differentiate the method from all previously proposed treatments.
The key for how to separate the actions of the antagonists comes from an understanding of how the antagonists act in the nervous system to produce benefits.
There are two basic processes through which long-term change is made in the organization of the nervous system as a result of experience: one causes learning by strengthening synapses; the other causes habituation and extinction by weakening synapses (see Sinclair, 1981). Experimental results also show that the two occur under different circumstances and follow different rules. Thus, extinction is not simply learning to do something else but rather a separate phenomenon. It also is distinct from forgetting; it is an active process for removing unsuccessful responses and requires the emission of the response in the absence reinforcement.
Our preclinical experimental results had shown that alcohol drinking is a learned behavior (Sinclair, 1974), and that opioid antagonists suppress alcohol drinking by mechanism of extinction (Sinclair, U.S. Pat. No. 4,882,335, Nov. 21, 1989; Sinclair, 1990). Extinction weakens only those responses that are made while reinforcement is blocked. There the method I proposed for treating alcoholism had the antagonist being administered just before the alcoholic drank alcohol.
Others in the field, however, believed that opioid antagonists block the craving for alcohol caused by an imbalance, either a deficiency in opioid receptor activity (Tractenberg and Blum, 1987; Volpicelli et al., 1990) or having too much opioid receptor activity (Reid and Hubbell, 1922). According to these theories, the antagonists would be effective if given during abstinence; they would block craving and the onset of drinking.
Our preclinical experiments had shown that giving opioid antagonists during abstinence not only failed to reduce subsequent drinking, but actually tended to increase subsequent drinking above control levels (Sinclair et al., 2003). The same result was found in our dual clinical trial (Heinola et al., 2001). Naltrexone was effective when paired with alcohol drinking, but naltrexone tended to be worse than placebo when given during abstinence. Similar results can be seen in the other clinical trials (Sinclair, 2001). The latest published count had 41 clinical trials that obtained significant results from using opioid antagonists in a manner allowing extinction; 37 trials using the antagonists in ways precluding extinction, however, got negative results; only 4 trials had results contrary to this conclusion (Fantozzi and Sinclair, 2004).
The mechanism causing the increase in alcohol drinking when antagonists are administered only during abstinence can be used to improve the efficacy of treatment. It can increase the strength of behaviors other than alcohol drinking, of behaviors that can compete with drinking and help fill the vacuum as drinking is extinguished. At the same time other behaviors that are reinforced by endorphins are protected from extinction. One problem noted in some of the clinical alcohol trials is a reduction in the patients' interest in sweets or carbohydrates, or in sex (Bohn et al. 1994; Balldin et al., 1997) This is probably caused by these behaviors being made while on naltrexone and thus, along with alcohol drinking, being partially extinguished. Naltrexone given to humans reduces their preference for saccharin (Arbisi et al., 1999)
The first step in our clinical use of selective extinction in alcoholism treatment is to have patients make a list of behaviors they find pleasurable. The clinician identifies the behaviors on the list that are probably reinforced by the opioidergic system and advises the patient to avoid engaging in these activities on the days when taking naltrexone and drinking. In the beginning of treatment, this is essentially every day.
After the treatment has reduced craving for alcohol, usually during the first month, the patient is advised to have a weekend, starting with Friday evening, with no naltrexone and drinking. Friday night and Saturday constitute a wash-out period for naltrexone to be removed from the body. On Sunday afternoon, the patient chooses some of the opioidergically-reinforced behaviors: eating a highly palatable meal, jogging, having sex, cuddling, cards, etc. As expected, patients usually report that the activities at this time are unusually enjoyable.
The patients can return to naltrexone and drinking on Monday. They are advised, however, to try the next week to have a longer period without naltrexone and drinking but with the alternative behaviors. A three-year follow-up showed that complying patients reported a maximum of 1.5±0.4 (SEM) days per week (Sinclair et al., 2000).
The example included here is a prior preclinical experiment in which the alternative opioidergically-reinforced behavior was saccharin drinking. Alcohol experienced rats had continual access to food and water. Alcohol solution was available for only an hour a day for 2 to 4 days. On the next day or two, saccharin solution instead was available. Naloxone (or saline for the control group) was injected prior to the alcohol session. During the first three weeks when the naloxone doses were in the range previously found to be effective, the alcohol drinking was practically abolished. Saccharin drinking in the same animals was significantly increased.